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Losartan potassium

Basic information Description References Safety Related Supplier
Losartan potassium Basic information
Losartan potassium Chemical Properties
  • Melting point:263-265°C
  • storage temp. Inert atmosphere,Room Temperature
  • solubility Freely soluble in water and in methanol, slightly soluble in acetonitrile.
  • form powder or crystals
  • Merck 14,5583
  • BRN 5845770
  • CAS DataBase Reference124750-99-8(CAS DataBase Reference)
Safety Information
  • Hazard Codes Xi
  • Risk Statements 36/37/38
  • Safety Statements 26-36/37/39
  • WGK Germany 3
  • RTECS NI6755100
  • HS Code 2933290000
Losartan potassium Usage And Synthesis
  • DescriptionAs a angiotensin II receptor antagonist, Losartan Potassium is the potassium salt of losartan with antihypertensive activity, which is mainly used in the therapy of high blood pressure (hypertension) and diabetic nephropathy. It functions by relaxing blood vessels so that blood can flow more easily. It is also effective to help protect the kidneys from damage caused by diabetes and lower the risks of stroke in patients suffering from hypertension and myocardial enlargement. Besides, recent study has suggested that losartan is beneficial to reverse age related dysfunction in maintaining normal blood pressure and cellular energy usage on mitochondria and it can probably be used to treat left ventricular hypertrophy. It may also be used as an alternative agent for the treatment of systolic dysfunction, myocardial infarction, coronary artery disease, and heart failure.
  • References
  • DescriptionLosartan potassium is the first potent and selective non-peptide angiotensin II (AT II) AT1 receptor antagonist introduced to the market as a once-daily oral antihypertensive. It is efficacious and long lasting in controlling blood pressure in spontaneous hypertensive rats, in patients with essential hypertension in addition to those patients with renal impairment. Since losartan functions by competitive antagonism at the level of receptor, which represents the most direct way of selectively inhibiting the renin-angiotensin system (RAS) independent of the source of AT II, its use has been reported to be free of the coughing side effect exhibited by the ACE inhibitors. In contrast to calcium channel blockers, losartan does not appear to cause ankle edema, headache and tachycardia. It is also reported to be in clinical trials for the treatment of heart failure. Other reports indicate that losartan may have potential efficacy as an anxiolytic, an antiglaucoma agent, in addition to in providing protection against stroke and in preventing the myointimal proliferative response of the vascular wall after coronary angioplasty and surgery.
  • Chemical PropertiesWhite to Off-White Crystalline Powder
  • OriginatorDuPont Merck (U.S.A.)
  • UsesA nonpeptide angiotensin II AT1-receptor antagonist. Antihypertensive.
  • Usesantihypertensive, AT1 angiotensin II antagonist
  • UsesCoronary vasodilator used in the diagnosis of coronary heart disease (adenosine A2A agonist).
  • Manufacturing Process2-Butyl-4-chloro-1-(2'-(tetrazol-5-yl)biphenyl-4-ylmethyl)-1H-imidazole-5- methanolpotassium was synthesized in 5 stages.
    1. Methyl 4'-methylbiphenyl-2-carboxylate (44.2 mmol), 0.5 N KOH in methanol (133 mmol), and water (50 mL) were mixed and refluxed under nitrogen. After 5 hours, the solvent was removed in vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers collected, dried (MgSO4) and the solvent removed in vacuo to yield 8.71 g of a 4'-methylbiphenyl-2-carboxylic acid, melting point 140.0-145.0°C.
    2. 4'-Methylbiphenyl-2-carboxylic acid (41 mmol) and thionyl chloride (411 mmol) were mixed and refluxed for 2 hours. The excess thionyl chloride was removed in vacuo and the residue was taken up in toluene. The toluene was removed by rotary evaporation. The crude acid chloride was then added slowly to cold (0°C) concentrated NH4OH (50 mL) so that the temperature was kept below 15°C. After 15 minutes of stirring, water (100 mL) was added and solids precipitated. These were collected, washed with water and dried under high vacuum over P2O5 to yield 7.45 g of a white solid, melting point 126.0-128.5°C. The above product amide (35 mmol) and thionyl chloride (353 mmol) were mixed and refluxed for 3 hours. The thionyl chloride was removed using the same procedure as described above. The residue was washed with a little hexane to yield 6.64 g of 4'-methyl-2-cyanobiphenyl, melting point 44.0- 47.0°C.
    3. 4'-Methyl-2-cyanobiphenyl (5.59 g) was brominated using benzoyl peroxide as an initiator. The product was recrystallized from ether to yield 4.7 g of 4'- bromomethyl-2-cyanobiphenyl, melting point 114.5-120.0°C.
    4. 4'-Bromomethyl-2-cyanobiphenyl (4.6 g) was alkylated onto 2-n-butyl-4- chloro-5-(hydroxymethyl)-imidazole. For separation of the product was used a flash chromatography in 1:1 hexane/ethyl acetate over silica gel. The regioisomeric products yielded 2.53 g of the faster eluting isomer. Recrystallization from acetonitrile yielded 1.57 g of analytically pure 2-n-butyl4-chloro-1-[2'-cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole, melting point 153.5 -155.5°C.
    5. 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)-methyl]-5-(hydroxymethyl)- imidazole (10 mmole), sodium azide (10 mmol), and ammonium chloride (30 mmol) were mixed in DMF (150 mL) under N2 at 100°C for 2 days, after which the temperature was raised to 120°C for 6 days. The reaction was cooled and 3 more equivalents each of ammonium chloride and sodium azide were added. The reaction was again heated for 5 days at 120°C. The reaction was cooled, the inorganic salts filtered, and the filtrate solvent removed in vacuo. Water (200 mL) and ethyl acetate (200 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layers were collected, dried (MgSO4) and the solvent removed in vacuo, to yield a dark yellow oil. The product was purified by flash chromatography in 100% ethyl acetate to 100% ethanol over silica gel to yield 5.60 g of a light yellow 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1Htetrazol-5-yl)biphenyl-4-yl)methyl]imidazole. Recrystallization from acetonitrile yielded 4.36 g of light yellow crystals which still melted broadly. The crystals were taken up in 100 mL of hot acetonitrile. The solid that did not dissolve was filtered off to yield 1.04 g of product as a light yellow solid, melting point of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole 183.5-184.5°C.
    2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole may be converted to potassium salt.
  • brand nameCozaar (Merck).
  • Therapeutic FunctionAntihypertensive
  • Biological ActivitySelective non-peptide angiotensin AT 1 receptor antagonist. Inhibits the contractile effects of angiotensin II on rabbit aorta and jugular vein (pA 2 = 8.27). Orally active antihypertensive agent.
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